4-oxo-4,5-dihydrothieno(3,2-c)pyridines

ABSTRACT

1. A COMPOUND OF THE FORMULA   4-(O=),5-R3,6-R2-4,5-DIHYDROTHIENO(3,2-C)PYRIDINE   WHEREIN R2 IS HYDROGEN, HALOGEN, CYANO OR DILOWERALKYLAMINO AND R3 IS HYDROGEN OR LOWERALKYL OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF PROVIDED THAT R2 IS NOT HYDROGEN OR HALOGEN WHEN R3 IS HYDROGEN.

United States Patent J. No Drawing. Filed Feb. 18, 1972, Ser. No.227,612 Int. Cl. C0711 63/18 US. Cl. 260-294.8 C 6 Claims ABSTRACT OFTHE DISCLOSURE Novel substituted-thieno[3,2-c]-pyridine asanti-inflammatory, anti-pyretic, analgesic and tranquilizing agents.Also included herein are pharmaceutical compositions containing saidthieno[3,2-c]-pyridine compounds as an active ingredient, and methods oftreating inflammation, fever, emotional disorders and pain in patientsby administering said compounds. Further encompassed are4-oxo-4,5-dihydrothieno[3,2-c]-pyridine and 4-chloro-4,5-dihydrothieno[3,2-c]-pyridine, possessing novel anti-inrflammatory,anti-pyretic, tranquilizing and analgesic activities.

This invention relates to novel substituted-thieno [3,2-c]-pyridines andmethods for preparing the same. Also included within the scope of theinvention are pharmaceutical compositions containing said thieno[3,2-c]-pyridine compounds as active ingredients. The novelthieno[3,2-c]-pyridines of the invention are potent antiinllammatory,anti-pyretic, tranquilizing and analgesic agents which are effective inthe method of counteracting inflammation, emotional disorders, pain andfever.

Numerous compounds have been widely used in the treatment ofinflammation, emotional disorders, pain and fever during the pastdecade. The compounds employed in said treatment have consisted of bothsteroids and nonsteroids. These compounds have been shown side effectsranging from a simple headache to psychic and gastrointestinaldisturbances.

In a continuous search for potent anti-inflammatory, anti-pyretic,tranquilizing and analgesic agents, we have found a class of novelthieno[3,2-c]-pyridines which are highly effective in the treatment ofinflammation, pain, emotional disorders and fever. The novelthieno[3,2-c]- pyridines are of value in the treatment of arthritic anddermatological disorders of like conditions responsive toanti-inflammatory drugs. In general, they are indicated for a widevariety of conditions where one or more of the symptoms of inflammation,fever, emotional disorders (anxiety, dissociative, conversion, phobic,depressive and obsessive compulsive) and pain are manifested. Includedwithin this category are diseases such as rheumatoid arthritis,osteo-arthritis, gout, infectious arthritis and rheumatic fever. Asindicated above, the compounds utilized in the practice of the inventionalso possess a useful degree of analgesic, tranquilizing andanti-pyretic activity.

Further encompassed within the scope of the invention are4-oxo-4,5-dihydrothieno[3,2-c1-pyridine and 4-chloro-4,5-dihydrothien0[3,2-c]-pyridine, compounds known to the art [BulL Soc.Chem. Belges 79 407-414 (1970) and Chemical Abstracts 73 120639 U(1970)] but having no disclosed pharmaceutical utility. These knowncompounds have unexpectedly been found to possess potentantiinflammatory, anti-pyretic, tranquilizing and analgesic activities.

The novel thieno[3,2-c]-pyridine compounds of the invention arerepresented by the following general structure:

3,845,065 Patented Oct. 29, 1974 "n ce wherein R and R are eachhydrogen, halogen, such as fluorine, bromine and the like, alkoxy, suchas methoxy, ethoxy, isopropyloxy, butoxy and the like, nitrile, hydroxy,nitro, amino, hydroxyalkyl, such as hydroxymethyl, hydroxyethyl,hydroxypropyl and the like, alkyl, such as methyl, P py ethyl, t-butyland the like, dialkylamino, such as dimethylamino, diethylamino,methylethylamino and the like, dialkenylamino, such as dibutenylamino,dipentenylamino, dipropenylamino and the like, alkylamino, such asmethylamino, ethylamino, butylamino and the like, arylamino, such asanilino, o,m or p-tolylamino, anisidino and the like, aralkylamino, suchas benzylamino, phenethylamino, o, m or p-methoxybenzylamino, o, m orp-halobenzylamino, heterocyclicamino, such as piperidino, morpholino,methylpiperazinyl, pyrrolidino, azepino and the like, alkenylamino, suchas butenylamino, propenylamino and the like, aroyl, such as benzoyl, o,m or p-halobenzoyl, o, m or p-methylthiobenzoyl,

aroylarnino, such as benzoylamino, o, m or p-halobenzoylamino, o, m orp-methoxybenzoylamino, o, m or p-methylthiobenzoylamino, acylamino, suchas acetylamino, propionylamino, butyrylamino and the like, acyl, such asacetyl, propionyl, butyryl and the like, mcrcapto, alkylthio, such asmethylthio, ethylthio, butylthio and the like, arylthio, such asphenylthio, o, m or p-tolylthio and the like, aralkylthio, such asbenzylthio, o, m or p-methylbenzylthio, 0, m or p-methoxybenzylthio,phenethylthio and the like, alkenylthio, such as butenylthio,propenylthio and the like, alkylsulfoxide, such as methylsulfoxide,ethylsulfoxide, propylsulfoxide and the like, alkenylsulfoxide, such asallylsulfoxide and the like, arylsulfoxide, such as phenylsulfoxide, o,m or p-tolylsulfoxide and the like, aralkylsulfoxide, such asbenzylsulfoxide, phenethylsulfoxide and the like, alkylsulfone, such asmethylsulfone, ethylsulfone, isopropylsulfone, butylsulfone and thelike, alkenylsulfone, such as butenylsulfone, propenylsulfone, and thelike, arylsulfone, such as phenylsulfone, o, m or p-tolylsulfone and thelike, aralkylsulfone, such as benzylsulfone, phenethylsulfone, o, m orp-rnethylbenzylsulfone and the like, carbamoyl, monoor dialkylcarbamoyl,such as methylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl,butylcarba-moyl and the like, arylcarbamoyl, such as phenylcarbamoyl,anisidinocarbamoyl and the like, aralkylcarbamoyl, such asbenzylcarbamoyl, o, m or p-methylbenzylcarbamoyl, phenethylcarbamoyl andthe like, monoor dialkenylcarbamoyl, such as propenylcarbamoyl,butenylcarbamoyl, pentenylcarbamoyl, dipropenylcarbamoyl and the like,

amidino, unreido, carbamoyloxy, N-alkylcarbamoyloxy, such asN-rnethylcarbamoyloxy, N-ethylcarbamoyloxy, N-isopropylcarbamoyloxy,N-butylcarbamoyloxy and the like, N-dialkylcarbamoyloxy, such asN-dimethylcarbamoyloxy, N-diethylcarbamoyloxy, N-dibutylcarbamoyloxy andthe like, haloalkyl, such as difluoromethyl, fiuoromethyl,trifluoromethyl, trichloromethyl, bromomethyl, chloromethyl,tribromoethyl and the like, sulfamoyl, alkylsulfamoyl, such asmethylsulfamoyl, ethylsulfamoyl, isopropylsulfamoyl, butylsulfamoyl andthe like, dialkylsulfamoyl, such as dimethylsulfamoyl, diethylsulfamoyl,methylethylsulfarnoyl, di-isopropylsulfamoyl and the like, haloalkoxy,such as trifluoromethoxy, difluoromethoxy, dibromoethoxy,dichloromethoxy, trifluoroethoxy, fluoromethoxy and the like,haloalkylthio, such as trifiuoromethylthio, difluoromethylthio,fluoromethylthio, bromomethylthio, dichloroethylthio, trifiuoroethylthioand the like, alkenyloxy, such as propenyloxy, ethenyloxy and the like,aryloxy, such as phenoxy, o, m or p-halophenoxy, 0, In or p-tolyloxy, 0,In or p-methoxyphenoxy and the like, aralkyloxy, such as benzyloxy,'phenethyloxy, o, m or p-methoxybenzyloxy, o, m or p-methylbenzyloxy andthe like, carboxy, carboxyalkyl, such as carboxymethyl, a-carboxyethyland the like, carboxyalkenyl, such as u-carboxy(ethylidenylacarboxy(butenyl) and the like, alkylaminoalkyl, such asethylaminoethyl, methylaminomethyl, methylaminopropyl, butylaminomethyl,isopropylaminomethyl and the like, dialkylaminoalkyl, such asdiethylaminoethyl, methylethylaminomethyl, dibutylaminoethyl,

dimethylaminoethyl, diethylaminobutyl and the like,alkylaminoalkylamino, such as ethylaminomethylamino,methylaminoethylamino, propylaminoethylamino, isopropylaminomethylamino,butylaminopentylamino and the like, dialkylaminoalkylamino, such asdiethylaminomethylamino, dimethylaminoethylamino,methylisopropylaminoethylamino, butylethylaminomethylamino,dimethylaminopropylamino and the like, aralkylaminoalkyl, such asbenzylaminomethyl, phenethylaminoethyl, o, m orp-methoxybenzylaminomethyl, o, m or p-halobenzylaminopropyl, o, m orp-methylbenzylaminomethyl and the like, diaralkylaminoalkyl, such asdimethoxybenzylaminomethyl, dibenzylaminoethyl, dihalobenzylaminopropyl,diphenethylaminomethyl and the like, aralkylaminoalkylamino, such asbenzylaminomethylamino, phenethylaminoethylamino, 0, m 01'p-methylbenzylaminomethylamino, o, m or p-methoxybenzylaminopropylaminoand the like, diaralkylaminoalkylamino, such asdibenzylaminomethylamino, diphenethylarninoethylamino,benzylphenethylaminopropylamino, di- 0, m orp-methylbenzylaminobutylamino, and

the like, haloalkyl, such as bromomethyl, chloroethyl, fluoropropyl,bromoethyl and the like, halocarbonyl, such as chlorocarbonyl,bromocarbonyl, fluorocarbonyl and the like, arylaminoalkyl, such asanilinomethyl, anisidinoethyl, o, m or p-tolylaminomethyl, o, m orp-haloanilinopropyl and the like, diarylaminoalkyl, such asdiphenylaminomethyl, di- 0, m or p-tolylaminoethyl, dior o, m orp-halophenylaminopropyl, di- 0, m or p-methoxyphenylaminomethyl and thelike, arylaminoalkylamino, such as anilinomethylamino,anisidinoethylamino, o, In or p-tolylaminoethylamino, o, m or phalophenylaminopropylamino, and the like, diarylaminoalkylamino, such asdiphenylaminomethylamino, phenylo, m or p-tolylaminoethylamino, o, m orp-halophenyl-o, m or p-methoxyphenylaminopropylamino and the like,alkyl, aralkyl or phenyl xanthylalkyl radical capable of forming a hissubstituent, such as methylxanthylmethyl, ethylxanthylpropyl,isopropylxanthylmethyl, phenylxanthylmethyl,

phenylxanthylpropyl,

benzylxanthylmethyl and the like; aryloxycarbonylalkyl, such asphenoxycarbonylmethyl,

o, m or p-tolyloxycarbonylethyl,

o, m or p-methoxyphenoxycarbonylpropyl,

o, m or p-halophenoxycarbonylbutyl and the like,aralkyloxycar-bonylalkyl, such as 'benzyloxycarbonylmethyl,

phenethoxycarbonylpropyl,

o, m or p-aminobenzyloxycarbonylbutyl,

o, n or p halophenethoxycarbonylmethyl and the R3 is hydrogen, alkyl,such as methyl,

ethyl,

propyl and the like, aralkyl, such as benzyl,

o, m or p-methylbenzyl,

phenethyl,

0, m or p-methoxybenzyl and the like, aryl, such as phenyl,

o, m or p-tolyl,

o, m or p-methoxyphenyl and the like, acyl, such as acetyl,

propionyl,

butyryl and the like, aroyl, such as o, m or p-halobenzoyl,

benzoyl and the like, alkoxyalkyl, such as methoxymethyl,

methoxyethyl,

propyloxymethyl and the like, aminoalkyl, such as aminoethyl,

aminopropyl,

aminobutyl and the like, carboxyalkyl, such as carboxymethyl,

carboxyethyl,

carboxypropyl,

carboxybutyl and the like, hydroxyalkyl, such as hydroxymethyl,

hydroxyethyl,

hydroxybutyl and the like, alkenyl, such as propenyl,

butenyl and the like, alkoxycarbonyl, such as methoxycarbonyl,

ethoxycarbonyl,

isopropyloxycarbonyl and the like, carbamoyl, carboxyalkoxy, such ascarboxymethoxy,

carboxyethoxy,

carboxyisopropyloxy and the like, mercaptoalkyl, such as mercaptomethyl,

mercaptoethyl,

mercaptoisopropyl,

mercaptobutyl and the like, alkylthioalkyl, such as methylthiomethyl,

methylthioethyl,

ethylthiomethyl,

ethylthioethyl,

isopropylthioethyl and the like, aralkylthioalkyl, such asbenzylthioethyl,

o, m or p-methylbenzylthioethyl,

o, m or p-methoxybenzylthiomethyl,

phenethylthioethyl,

benzylthiomethyl and the like, aralkylsulfinylalkyl, such asbenzylsulfinylethyl,

phenethylsulfinylethyl,

0, m or p-methylbenzylsulfinylmethyl,

o, m or p-methoxybenzylsulfinylethyl,

o, m or p-halobenzylsulfinylethyl,

o, m, or p-aminobenzylsulfinyl and the like;

R4 is hydrogen, amino, halogen, such as chlorine,

bromine and the like; alkoxy, such as methoxy,

p p y.

butoxy,

isopropoxy,

ethoxy and the like; aralkyloxy, such as benzyloxy,

phenethyloxy,

0, m or p-methylbenzyloxy,

o, m or p-methoxybenzyloxy,

o, m or p-halobenzyloxy and the like, heterocyclicamino, such aspiperidino,

morpholino,

methylpiperazinyl,

pyrrolidino,

azepino and the like, and aryloxy, such as phenoxy,

o, 'm or p-tolyloxy,

o, m or p-methoxyphenoxy,

o, m or p-halophenoxy and the like;

with the following provisos:

1. When R is hydrogen, at least one of R and R are other than hydrogen.2. When R is halogen, R is other than halogen and hydrogen. 3. When R ishalogen in the 2-position of the thienopyridine nucleus in Formula I, atleast one of R and R are other than hydrogen.

4. When R is halogen in the 2-position of the thienopyridine nucleus inFormula II, R is other than hydrogen or R is other than chlorine.

5. When R is halogen, at least one of R and R are other than hydrogen.

This invention may be better understood from the details shown below.

The novel compounds of the invention are prepared by employing7-bromo-4-oxo-4,S-dihydrothieno[3,2-c]-pyridine wherein x is 0 or7-bromo-2 or 3-halo-4,S-dihydrothieno[3,2-c]pyridine wherein x is 1 (A)as the starting material. Said starting material (A) is treated with acyanoforming reagent to obtain the corresponding 7-cyano 4-oxo-4,5dihydrothieno[3,2-c]-pyridine (B). The cyano substituent of the compoundthus obtained is hydrolyzed to obtain the corresponding7-car'boxy-4-oxo-4,S-dihydrothieno[3,2-c]-pyridine (C). This car'boxycompound is then treated with an acid halide-forming reagent wherebythere is obtained the 7-acid halide-4-halothieno[3,2-01- pyridine (D).Treating the compound thus obtained with a reducing agent yields thecorresponding 7-hydroxyalkyl- 4-ha'lothieno[3,2-c]-pyridine (E). Thiscompound is then treated with a halogenating reagent to obtain thecorresponding 7-haloalkyl-4-halothieno[3,2-c] pyridine (F). Treatingthis compound with an alkyl, aryl or aralkylxanthylalkyl-forming reagentyields the corresponding 7- alkyl, aralkyl orarylxanthylalkyl-4-halothieno[3,2-c]-pyridine (G). The xanthyl compound(G) is then treated with a his sulfide-forming reagent to obtain thecorresponding bis 4-halo 7 thioalkylthieno[3,2-c1-pyridine (H).

Compound (D), 7-chlorocarbony1-4-halothieno[3,2-c]- pyridine is treatedwith a carbamoyl-forming reagent to obtain the corresponding7-carbamoylthieno[3,2-c]-pyridine (I). Said carbamoyl compound (I) isthen treated with an amino-forming reagent to obtain the correspondingcompound, 7-carba-moyl 4 aminothieno[3,2-c]- pyridine (J). Also,compound (D) can be treated either with an alkoxy, aryloxy oraralkyloxy-forming reagent to obtain the corresponding 7-alkoxycarbonyl,aryloxycarbonyl or aralkyloxycarbonyltriono[3,2-0] pyridine (D); anamide-forming reagent to obtain the corresponding 7- alkylcarbamoyl,aralkylcarbamoyl or arylcarbamoylthieno[3,2-c]-pyridine (K); or ahydrolyzing reagent to obtain the corresponding 7-carboxythieno[3,2-c]-pyridine (0).

Compound (B), 7-cyano-4-oxo-4,S-dihydrothieno[3,2- c]-pyridine, istreated with a halogenating reagent to obtain the corresponding 7-cyano-2 or 3-ha1othieno[3,2-c]- pyridine (A). The 2 or 3-halo substituent ofthe compound thus obtained is then converted to the corresponding 2 or3-cyanothieno[3,2-c] -pyridine (B'). Also, compound (B) can be treatedwith an R substituent to obtain the corresponding 7-cyano-5-R 4-oXo-4,5dihydrothieno[3,2- cJ-pyridine (Z).

Starting material (A), 7-bromo-4-oxo-4,5 dihydrothieno[3,2-c]-pyridine,is treated with a halofonming reagent to obtain7-bromo-4-halothieno-[3,2-c] -pyridine (R). This compound (R) is thentreated either with an alkoxy, aryloxy or aralkyloxy-forming reagent toobtain the corresponding 4-alkoxy, aryloxy or aralkyloxythieno[3,Z-cJ-pyridine (W or Y); or an amino-forming reagent to obtain thecorresponding 4-aminothieno[3,2-c]-PY dine (X). Treating startingmaterial (A) with an alkoxycarbonylalkyl, aralkoxycarbonylalkyl oraryloxycarbonylalkyl-forming reagent yields the corresponding4-alkoxycarbonylalkyl, aralkoxycarbonylalkyl oraryloxycarbonylalkylthieno[3,2-c]-pyridine (V). Compound (U), 7- bromo-2or 3-halo-4-oxo-4,S-dihydrothieno[3,2-c]-pyridine, is obtained bytreating compound (A), 7-bromo-4- oxo-4,5 dihydrothieno[3,2-c]-pyridine, with a halogenating reagent. To obtain7-bromo-4-oxo-5-alkylcarbonylalkyl, aralkylcarbonylalkyl orarylcanbonylalkylthieno- [3,2-c]-pyridine (T), compound (A) is treatedwith an alkylcarbonylalkyl, aralkylcarbonylalkyl orarylcarbonylalkyl-forming reagent. Treating compound (A) with anunsubstituted or substituted-mono or disubstituted-aminoalkylaminoyields the corresponding 7-amino-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine (S). Also, treating compound (A),7-bromo-4-oxo-4,S-dihydrothieno[3,2]-PY idine with either an R -formingreagent, an alkylthio, arylthio or aralkylthio-forming reagent, or anunsubstituted or substituted-amino-forming reagent, there is obtainedthe corresponding 7- bromo-4-oXo-5-R -4,S-dihydrothieno[3,2-c]-pyridine(Q); 7-alkylthio, ara'lkylthio orarylthio-4-oxo-4,5dihydrothieno-[3,2-c]pyridine (P); or

10 7-substituted orunsubstituted-amino-4-ox0-4,S-dihydrothieno[3,2-c]-pyridine (O and N),respectively.

To obtain 4-oxo-5-R -4,S-dihydrothieno[3,2-c]-pyridiue (M), compound (A)is dehalogenated to yield 4-oXo-4,5- dihydrothieno[3,2-c]-pyridine (L),which is then treated with an R -forming reagent to obtain the product(M).

Flo-w Sheet I represents the general sequence for the preparation of thenovel compounds of the invention.

H H o cum. cym 1 m (cm), ttfio. l- '7"). N l l l p Y (K) Y 53 (Has- S lu l Steps 1.1 and 1.27

The reaction is performed in an inert solvent such as benzene, toluene,dimethylformamide, tetrahydrofuran and the like, in the presence of acyano-forming reagent such as cuprous cyanide, alkali cyanide such aspotassium, sodium and the like, at temperatures ranging from near refluxto reflux. Of particular preference is the combination of cuprouscyanide and dimethylformamide at reflux until the reaction is complete.

Step 1.2

The reaction is performed in the presence of a concentrated or aqueousacid such as sulfuric, hydrochloric and the like, at ambienttemperatures. Of particular preference is concentrated sulfuric acid atroom temperature.

Step 1.3

The reaction is performed with or Without an inert solvent such asether, benzene, and the like, and an acid halide-forming reagent such asphosphorus trichloride, phosphorus pentachloride, thionyl chloride,phosphorus tribromide, phosphorus oxychloride, and the like, attemperatures ranging from room temperature to reflux. Of particularpreference is phosphorus oxychloride at reflux until the reaction iscomplete.

Step 1.4

The reaction is performed in an inert solvent such as benzene, toluene,ether, tetrahydrofuran, and the like, in the presence of a reducingagent such as lithium aluminum hydride, sodium borohydride, diborane,aluminum hydride and the like, at temperatures ranging from near refluxto reflux. Of particular preference is lithium aluminum hydride atreflux until the reaction is complete.

Step 1.5

The reaction is performed with a hydrohalic acid such as hydrobromicacid, hydrochloric acid and the like, at temperatures ranging from 40 C.to near'reflux. Of particular preference is hydrobromic acid at nearreflux until the reaction is complete.

Step 1.6

The reaction is performed with water and an alkyl xanthic acid potassiumsalt, the alkyl substituent being represented by methyl, ethyl, propyl,and the like, at temperatures ranging from 15 C.-50 C. Of particularpreference is ethyl xanthic acid potassium salt at room temperatureuntil the reaction is complete.

Step 1.7

The reaction is performed with an inert alcohol solvent such as ethanol,methanol, butanol, benzyl alcohol and the like, in the presence of abase such as ammonium hydroxide, sodium hydroxide, and the like, attemperatures ranging from 0 C. to C. Of particular preference is thecombination of ethanol and ammonium hydroxide at room temperature untilthe reaction is complete.

Step 1.8

The reaction is performed with or Without an inert solvent such asWater, dimethylformamide, ethanol, benzene, toluene and the like, in thepresence of a base such as ammonium hydroxide, methylamine, benzylamine,aniline and the like, at temperatures ranging from 10 C. to 50 C. Ofparticular preference is ammonium hydroxide at room temperature untilthe reaction is complete.

Step 1.9

The reaction is performed with or without an inert solvent such asbenzene, dimethylformamide, toluene, and the like, in the presence of anamino substituent such as piperidine, azepine, morpholine, ammonia,aniline, dimethylamine, benzylamine and the like, at temperaturesranging from 50 C. to reflux. Of particular preference is piperidine atnear reflux until the reaction is complete.

Step 1.10

The reaction is performed in an inert solvent such as benzene, toluene,benzyl alcohol, methanol, ethanol, tetrahydrofuran and the like, with anamino-forming substit uent such as methylamine, aniline, benzylamine andthe like, at temperatures ranging from 10 C. to 40 C. Of particularpreference is the combination of methanol and aniline at roomtemperature until the reaction is complete.

Step 1.11

The reaction is performed by hydrogenation over a catalyst such aspalladium-on-carbon, platinum, Raney nickel and the like, in thepresence of an inert solvent such as methanol, ethanol, propanol,butanol, benzene, toluene, tetrahydrofuran, and the like, attemperatures ranging from 0 C. to near reflux. Of particular prefer- 13ence is the combination of palladium-on-carbon and methanol at roomtemperature until the reaction is complete.

Steps 1.12, 1.16, and 1.25

The reaction is performed in an inert solvent such as ether,dimethylsulfoxide, tetrahydrofuran, benzene, toluene and the like, inthe presence of a base such as sodium hydride, sodium amide, potassiumhydroxide and the like, with an alkyl halide such as methyl iodide,propyl bromide, butyl iodide and the like, or an alkenyl halide such asallyl bromide, vinyl iodide, propenyl chloride and the like, attemperatures ranging from C. to 60 C. Of particular preference is thecombination of dimethylformamide, sodium hydride and methyl iodide atroom temperature until the reaction is complete.

Steps 1.13, 1.14 and 1.18

The reaction is performed with or without an inert solvent such asdimethylsulfoxide, tetrahydrofuran, benzene, toluene and the like, inthe presence of a base such as sodium amide, potassium hydroxide,3-dimethylaminepropylamine, piperidine, dimethylamine, methylamine,benzylamine, aniline and the like, at temperatures ranging from roomtemperature to 200 C.

Step 1.15

The reaction is performed with a cuprous alkyl mercaptide complex suchas cuprous methyl sulfide, cuprous ethyl sulfide and the like, attemperatures ranging from 80 C. to reflux. Of particular preference iscuprous methyl mercaptide complex at reflux until the reaction iscomplete.

Step 1.17

The reaction is usually performed without a solvent in the presence of ahalogenating reagent such as phosphorus oxychloride, phosphorustrichloride, thionyl chloride, phosphorus tribromide and the like, attemperatures ranging from room temperature to near reflux. Of particularpreference is phosphorus oxychloride at near reflux until the reactionis complete.

Step 1.19

The reaction is performed with an inert solvent such as benzene, ether,dimethylformamide, tetrahydrofuran, and the like, and a base such assodium hydride, sodium amide and the like, in the presence of analkylcarbonylalkyl, alkylcarbonylaryl or alkylcarbonylaralkyl-formingreagent such as oc-ChlOIOaCGtOPhCDOIIG, a-bromoacetophenone,bromomethylbenzylketone, ,B-chloroethylmethylketone and the like, attemperatures ranging from C. to 80 C. Of particular preference is thecombination of dimethylformamide, sodium hydride and a-bromoacetophenoneat room temperature until the reaction is complete.

Steps 1.20 and 1.26

The reaction is performed with an inert solvent such as benzene,dimethylformamide, toluene, tetrahydrofuran, ether and the like, in thepresence of a halogenating reagent such as N-bromosuccinimide,N-chlorosuccinimide, chlorine, N-bromophthalimide and the like, attemperatures ranging from room temperature to near reflux. Of particularpreference is the combination of dimethylformamide andN-bromosuccinimide at 60 C. until the reaction is complete.

Step 1.21

The reaction is performed with an inert solvent such as ether, benzene,tetrahydrofuran, dimethylformamide, ethanol and the like, and a basesuch as sodium amide, sodium hydride and the like, in the presence of analkoxycarbonylalkylhalide, aralkoxycarbonylalkylhalide orphenoxycarbonylalkylhalide and the like, at temperatures ranging from 10C. to 80 C. Of particular preference is the combination ofdimethylformamide, sodium hydride and methylbromoacetate at roomtemperature until the reaction is complete.

Steps 1.22 and 1.24

The reaction is performed in an inert solvent such as ethanol, benzene,toluene, methanol, tetrahydrofuran, benzyl alcohol and the like, with abase such as sodium hydride, sodium amide, and the like, in the presenceof an alkoxy, aryloxy or aralkoxy-forming reagent such as sodiummethoxide, benzyl alcohol, phenol, sodium ethoxide and the like, attemperatures to near reflux until the reaction is complete.

Step 1.23

The reaction is performed with or without an inert solvent such asbenzene, toluene, tetrahydrofuran, dimethylformamide and the like, andan amino-forming reagent such as piperidine, methylamine, dimethylamine,aniline, azepine, morpholine and the like, at temperatures ranging fromroom temperature to reflux. Of particular preference is piperidine atnear reflux until the reaction is complete.

Step 1.28

The reaction is performed in a ketone solution such as acetone,ethylmethyl ketone, hexanone, and the like, and water at temperaturesranging from 10 C. to near reflux. Of particular preference is thecombination of acetone and water at room temperature until the reactionis complete.

Step 1.29

The reaction is performed with or without an inert solvent such asbenzene, tetrahydrofuran, dimethylformamide, ether, methylene chlorideand the like, in the presence of an alkoxy, aralkoxy or aryloxy-formingreagent such as methanol, benzyl *alcohol, phenol and the like, attemperatures ranging from room temperature to C. (preferably 40 C.).

Representative compounds of the invention are:7-dimethylamin0-4-oxo-4,S-dihydrothieno[3,2-c]-pyridine 7-pi-peridino-4-oxo-4,5 -dihydro thieno 3 ,2-c] -pyridine 7 -me thylthio-4-oxo-4,5 -dihydro thieno [3 ,2-c] -pyridine 7 -phenylthio-4-oxo-4,S-dihydrothieno [3 ,2-c] -pyridine7-benzylthio-4-oxo-4,S-dihydrothieno[3,2-c]-pyridine 7 -bromo-4-oxo-5-methyl-4, S-dihydrothieno [3 ,2-c]

pyridine 7 -bromo-4-oxo-5 -benzyl-4,5-dihydrothieno [3 ,2-c]

pyridine 7-bromo-4-oxo-5-phenyl-4,S-dihydrothienol[3,2-c]- pyridine7-cyano-4-oxo-4,S-dihydrothieno [3,2-c1-pyridine 7(3-dimethylaminopropylamino)-4-oxo-4,5-

dihydrothieno 3 ,2-c] -pyridine7-bromo-4-oxo-5-phenacyl-4,S-dihydrothienol[3,2-c1- pyridine7-bromo-4-chlorothieno[3,2-c]-pyridine2,7-dibromo-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine3,7-dibromo-4-oxo-4,S-dihydrothieno[3,2-c]-pyridine5-methyl-4-oxo-4,5dihyd rot-hieno 3 ,2-c] -pyridine 5-b enzyl-4-oxo-4,S-dihydrothieno 3 ,2-c] -pyridine 5-phenyl-4-oxo-4,S-dihydrothieno 3,2-c] -pyridine 7-bromo-4-methoxythieno[3,2-c1-pyridine 7-bromo-4-o,m orp-tolyloxythieno [3,2-c] -pyridine 7-bromo-4-benzyloxythienol 3 ,2-c]-pyridine 7-bromo-4-phenoxythieno [3 ,2-c] -pyridine7-brom-o-4-piperidinothieno [3 ,2-c] -pyridine7-bromo-4-azepinothieno[3,2-c1-pyridine 7-bromo-4-anilinothieno [3 ,2c]-pyr-idine 7-cyano-2-brorno-4-oxo-4,S-dihydrothieno[3,2-c]-pyridine7-hydroxy-2-bromo-4-oxo-4,S-dihydrothieno [3,2-c]

pyridine 7-cyano-4-oxo-5-methyl-4,S-dihydrothieno[3,2-c]- pyridine 7-cyano-4-oxo-5-benzyl-4,5-dihydrothieno[3,2-c1- pyridine 7-cy-ano-4-oxo-5 -pheny1-4, 5 -dihydrothieno[ 3 ,2-c] pyridine2,7-dicyano-4-oxo-4, S-dihydro thieno [3 ,2-c] -pyr1d1ne 7-carboxy-4-oxo-4,5 -dihydrothieno [3 ,2-c] pyridine7-phenethoxy-4-oxo-4,S-dihydrothieno [3 ,2-c] -pyr1d1ne 7-phenethoxy-4-oxo-5-methyl-4, S-dihydrot-hieno [3 ,2-c]

pyridine 7-chloroc arbonyl-4-chlorothieno [3 ,2-c] pyridine 7-trifiuoromethylthi-o-4-chloro thieno [3 ,2-c] pyridine7-oarboxy-4-chlorothieno 3 ,2-c] -pyridine 7 -aceto-4-chlorothieno [3,2-c] pyridine 7-carb amoyl-4-chlorothieno [3 ,2-c] -pyridine 7-dimethylcarbamoyl-4-chlorothieno [3 ,2-c] -py1-i dine7-dimethylcarbamoyl-4-bromothieno [3,2-c1-pyridine 7-oarbamoyl-4-aminothieno 3 ,2-c] pyridine 7-carb amoyl-4-piperidinothieno [3,2-c] -pyridine methyl-4-chlorothieno 3,2-c] -pyricline-7-carboxylatebenzyl-4-chlorothieno [3 ,2-c] -pyridine-7-carboxyl atephenyl-4-chlorothieno 3, 2-c] -pyridine-7-c arb oxyl'atemethyl-4-bromothieno[ 3 ,2-c] -pyridine-7-earboxyl a-te7-phenyl-carba-moyl- 4-ch1orothieno 3 ,2-c] pyridine7-hydroxymethyl-4-ch'lorothieno 3 ,2-c] pyridine7-hydroxyethyl-4-chlorothieno [3 ,Z-c] pyridine7-bromomethyl-4-chlorothieno[ 3 ,2-c] pyridine7-iodomethyl-4-chlorothieno 3 ,2-c] pyridine 7- ethylxanthylmethyl-4-chlo r thieno [3 ,2-c] pyridine 7-benzylxanthyl-methyl-4-chlorothieno 3 ,2-c] pyridine7-benzylxanthylmethyl-4-bromothieno 3 ,2-c] pyridine7-phenylxanthylmethyl-4-chlorothieno [3 ,2-c] -pyridine bis-4-chloro-7thiomethylthien-o [3 ,Z-c] pyridine bis-4-chloro-7-t-hioethylthieno [3,2-c] pyridine 7-di-methyl-amino-4-oxo-5-anilinomethyl-4-di'hydrothieno- [3 ,2-c] pyridine 7 -dimethyl amino-4-oxo-5 -benzylaminoethyl-4, S-dihydrothieno [3 ,Z-c] pyridine 7 -amino-4-oxo-5-ethyl-aminomethyl-4, 5- dihyd-rothieno [3 ,Z c] -pyridine 7-piperidino-4-oxo-5-methyl-4,S-dihydrothieno [3 ,2-c]

pyridine 7-piperidino-4-oxo-5-acetyl-4,S-dihydrotbieno 3,2-c]

pyridine 7-b enzoyl-4 oxo-5carb oxylalkyl-4,S-dihydrothieno- 3,2-c]-pyridine 7-b enzoyl-4-oxo- S-benzylcarb onyl-alkyl-4,5-dihydrothieno [3,2-c] pyridine 7-cyano-4-oxo-5-methylcarb onylmethyl-4,5-dihydrothieno[3 ,2-c] -pyridine 7-dimethylamino-4-oxo-5-methylcarbonylmethyl-4,5-dihydrothieno 3 ,2-c] pyridine 7-met-hylaminoethyl-amino-4-oxo-5 methyl-4, S-dihydrothieno 3,2-c] pyridine S-methyl-(7-bromo-4-oxo-4,5-dihydrothieno 3,2-c]

pyridine) -acetate 7-cyano -4-oxo-2-bromothieno [3 2-c] -pyridine Thecompounds of this invention are administered orally, topically,intravenously or intnamuscularly in the treatment of inflammation,fever, anxiety and pain. Of particular preference is the oral formranging from 10 to 2000 mg./kg. of body weight per day. Of preference is50-500 mg./kg. of body weight per day for varying periods of treatmentas required. Comparable amounts of the compounds may be administered intopical or parenteral forms.

For these purposes, the compounds of the invention may be administeredorally, topically and parenterally in dosage unit formualtionscontaining conventional nontoxic pharmaceutically acceptable carriers,adjuvants and vehicles. The term parenter ally as used herein includesintravenous or intramuscular. In addition to the treatment ofwarm-blooded animals such as mice, rats, horses, dogs, cats, etc., thecompounds of the invention are effective the treatment of humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide a pharmaceutically elegant andpalatable preparation. Tablets contain the active ingredient inadmixture With non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be,for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, maize starch or alginic acid;binding agents, for example, starch, gelatin or acacia; and lubricatingagents, for example, magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the 'gastro-intestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example, arachis oil, peanut oil, liquid paraflin orolive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be naturallyoccurring phosphatide, forexample, lecithin, or condensation products of an alkylene oxide withfatty acids, for example, polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol mono-oleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example, polyoxyethylene sorbitanmono-oleate. The said aqueous suspensions may also contain one or morepreservatives, for example, ethyl or npropyl p-hydroxy benzoate, one ormore coloring agents, one or more flavoring agents and one or moresweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil, orcoconut oil, or in a mineral oil such as liquid paraflin. The oilsuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily 17 phase may be a vegetable oil, forexample, olive oil or arachis oils, or a mineral oil, for example,liquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example, gum acacia or gum tragacanth,naturally-occurring phosphatides, for example, soya bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example, sorbitan mono-oleate, and condensation productsof said partial esters With ethylene oxide, for example, polyoxyethylenesorbitan mono-oleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, sorbitol or sucrose. Such formulations may alsocontain a demulcent, a preservative and flavoring and coloring agents.

For intravenous and intramuscular administrations, the pharmaceuticalcompositions may be in the form of a sterile injectable preparation, forexample, as a sterile injectable aqueous or oleagenous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butane diol. Among the acceptable vehicles and solvents that maybe employed are water, Ringers solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic monoor di-glycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom mg. to grams of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 175 mg. to about 1.75 g. of activeingredient. Comparable amounts of the compounds may be administered intopical or parenteral forms.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

The starting material employed in the invention is represented bycompound (A) which is shown in Flow Sheet I. Said starting material isknown and processes for its preparation can be found in the literature.For example, see Bulletin des Societes Chemiques Belges 79, 407-14(1970) and Chemical Abstracts 73, 120639 U (1970).

The following examples illustrate the preparation of the variousthieno[3,2-c]-pyridine compounds described herein as anti-inflammatory,anti-pyretic, tranquilizing and analgesic agents. The examples should beconstrued as illustrations of the invention rather than limitationsthereof.

EXAMPLE 1 4-Oxo-4, S-dihydrothieno [3 ,2-c] -pyridine A solutioncontaining 9.2 g. of 7-bromo-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine in300 ml. of methanol and 4.0 g. of potassium acetate is hydrogenated inthe presence of 1 g. of 10% palladium-on-charcoal. After the theoreticalamount of hydrogen has been absorbed the catalyst is removed byfiltration, the solvent evaporated and the residue washed with water.Crystallization from methano gives crystals of4-oxo-4,5-dihydrothieno[3,2-cjpyridine, m.p. 208-209 C.

EXAMPLE 2 7-Dimethylamino-4-oxo-4,5-dihydrothieno [3,2-c1- pyridine Amixture which contains 9 g. of 7-bromo-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine and ml. of 40% dimethylamine is heated ina bomb at 170 C. for 24 hours. The solvent is evaporated and the solidresidue washed with water and then crystallized from methanol to yieldthe product, mp. 210-211 C.

When 7-brom0 4 oxo-5-benzyl-4,5-dihydrothieno [3,2-c]-pyridine, 7-bromo4 oxo-5-methyl-4,5-dihydro thieno[3,2-c]-pyridine, 7-bromo 4oxo-5-ethyl-4,5-dihydrothieno[3,2-c]-pyridine or7-bromo-4-oxo-5-benzyl-4,5- dihydrothieno[3,2-c]-pyridine is substitutedfor 7-bromo- 4-oxo-4,5-dihydrothieno[3,2-c]-pyridine, there is obtained7-dimethylamino 4 oxo 5 benzyl-4,5-dihydrothieno [3,2-c]-pyridine,7-dimethylamino 4 oxo-5-methyl-4,5- dihydrothieno 3,2-c] -pyridine,7-dimethylamino-4-oxo-5- ethyl 4,5 dihydrothieno[3,2-c]-pyridine or7-dimethylamino-4-oxo-5-benzyl-4,5 dihydrothieno[3,2-c]-pyridine,respectively.

EXAMPLE 3 7-Piperidino-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine A mixtureof 10 g. of 7-bromo-4-oxo-4,5-dihydrothieno [3,2-c1-pyridine and 75 ml.of piperidine is heated in a bomb at 160 C. for 60 hours. After theexcess piperidine is removed in vacuo, water is added to the residue andthe product crystallizes. It is then crystallized from ethanol and thenethyl acetate nad melted .at 188-189 C. with a softening at 165 C.

When ammonia, aniline, benzylamine, azepine, morpholine,methylpiperazine or pyrrolidine is substituted for piperidine, there isobtained 7-amino-4-oxo-4,S-dihydrothieno[3,2-c]-pyridine,7-anilino-4-oxo-4,S-dihydrothieno [3,2-c]-pyridine,7-benzylamino-4-oxo-4,5-dihydrothieno [3,2-c]-pyridine, 7-azepino 4oxo-4,5-dihydrothieno [3,2-c]-pyridine, 7morpholino-4-oxo-4,5-dihydrothieno [3,2-c]-pyridine, 7methylpiperazino-4-oxo-4,5-dihydrothieno[3,2-c] -pyridine or7-pyrrolidino-4-oxo-4,S-dihydrothieno[3,2-c] -pyridine, respectively.

EXAMPLE 4 7-Methylthio-4-oxo-4,5-dihydrothieno[ 3,2-c] -pyridine Thecuprous methyl mercaptide is prepared by heating, under reflux, withgood stirring, 4.0 g. of copper powder, 60 ml. of lutidine and 7 ml. ofmethyl disulfide at C. for 4 hours. The mixture is cooled and 12.5 g. of7-bromo-4-oxo-4,5 dihydrothieno[3,2-c]-pyridine added and the mixturerefluxed for 19 hours. The solvents are removed in vacuo and the blackgum residue stirred with 200 ml. of 2.5 N sodium hydroxide at 70 C. for15 hours. The liquid is decanted from the dark oil and extracted withether to remove any remaining lutidine and then the alkaline solution isneutralized with hydrochloric acid. The resulting precipitate iscrystallized twice from ethanol, mp. 207-211 C.

When benzyl disulfide or phenyl disulfide is substituted for methyldisulfide, there is obtained 7-benzylthio-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine or 7-phenylthio-4-oxo-4,5-dihydrothieno[3,2-c] -pyridine respectively.

EXAMPLE 5 7-Bromo-4-oxo-5 -methyl-4, 5 -dihydrothieno [3 ,2-c] pyridineA mixture of 5 g. of 7-bromo-4-oxo-4,S-dihydrothieno [3,2-c]-pyridine,100 ml. of acetone and 5 g. of anhydrous potassium carbonate is refluxedwith stirring and 10ml. portions of methyl iodide added three times over6 hours. No total solution occurs. The precipitate is removed by EXAMPLE6 7-Cyano-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine A mixture of 25 g. of7-bromo-4-oxo-4,S-dihydrothieno [3,2-c]-pyridine, 350 ml. ofdimethylformamide and 21 g. of cuprous cyanide is heated under refluxfor 18 hours. This solution is poured into a solution containing 2 g. offerric chloride, 300 ml. of water, and 50 ml. of concentratedhydrochloric acid. After 20 minutes at 65-70 C., a liter of water isadded and the mixture cooled, filtered, and the precipitate washed withwater. This crude material can be used in many reactions, but it can bepurified by crystallization from a large quantity of acetone, m.p.285287 C.

EXAMPLE 7 7-(3-Dimethylaminopropylamino) 4oxo-4,5-dihydrothieno[3,2-c]-pyridine, 1,5-naphthalene disulfonic acidsalt A mixture of g. of 7 bromo-4-oxo-4,5-dihydrothieno[3,2-c]-pyridineand 60 g. of 3-dimethylamino propylamine is heated at 160 C. for 60hours. The solvent is removed in vacuo and the residue dissolved in 25ml. of 2.5 N sodium hydroxide. This basic solution is extracted withether several times to remove any excess amine. The sodium hydroxidesolution is then neutralized with 28 ml. of 2.5 N hydrochloric acid, andthen extracted 4 times with chloroform. This chloroform solution iswashed with water, dried, and then a solution of 1.5-nahthalenedisulfonic acid in methanol is added. The precipitate is removed byfiltration and crystallized from methanol-water, or water alone, m.p.171-173 C.

EXAMPLE 8 7-Bromo-4-oxo-5-phenacyl-4,S-dihydrothieno[3,2-c1- pyridine Toa solution of 6.9 g. of 7-bromo-4-oxo-4,S-dihydrothieno[3,2-c]-pyridinein 75 ml. of dimethylformamide is added 1.5 g. of a 50% emulsion ofsodium hydride. After the sodium hydride is dissolved and thetemperature has fallen to room temperature, 6 g. of a-bromo-acetophenoneis added. The temperature rises to 45 C. and after 2 hours when thetemperature is down to room temperature, 75 ml. of methanol and 75 ml.of water are added. The resulting crystalline precipitate is removed byfiltration and heated in 200 ml. of boiling methanol. Four grams do notdissolve and are crystallized from 400 ml. of absolute ethanol, m.p.2lO-211 C.

EXAMPLE 9 7-Bromo-4-chlorothieno[3,2-c]-pyridine A solution of 2 g. of 7bromo-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine and ml. of phosphorusoxychloride is heated on the steam-bath for 2 hours. It is then pouredonto ice and after the decomposition of the phosphorus oxychloride, thesolid is removed by filtration. The product crystallizes from methanol,m.p. 1141l5 C.

EXAMPLE 1O 2,7-Dibromo-4-oxo-4,S-dihydrothieno [3 ,2-c] -pyridine To asolution of 2.3 g. of 7-bromo-4-oxo-4,S-dihydrothieno[3,2-c]-pyridine in60 ml. of dimethylformamide at 60 C. is added 1.9 g. ofN-bromosuccinimide. The prodnot begins to crystallize from the warmsolution in 5 minutes. After cooling and filtering, the product iscrystallized from hot dimethylformamide, m.p. 295296 C.

When N-chlorosuccinimide or N-iodosuccinimide is substituted forN-bromosuccinimide, there is otbained 7- bromo-Z-chloro 4oxo-4,5-dihydrothieno[3,2-c]-pyridine or 7bromo-2-iodo-4-oxo-4,5-dihydrothieno[3,2-c]- pyridine, respectively.

EXAMPLE 1 1 S-Methyl- 7-bromo-4-oxo-4,S-dihydrothieno 3,2-c] pyridine-acetate To a mixture of 6.9 g. of7-bromo-4-oxo-4-S-dihydothieno[3,2-c]-pyridine in 75 ml. ofdimethylformamide is added 1.5 g. of a 50% emulsion of sodium hydride.When all the sodium hydride has dissolved, and the solution has returnedto room temperature, 5 ml. of methyl bromo acetate is added. Thetemperature rises to 45 C. and when it goes down to room temperature,200 ml. of water is added and an oil separates. The mother liquor isdecanted and crystals separate. They are recrystallized from ethylacetate, m.p. 107108 C.

When benzyl bromo acetate or phenylethyl bromo acetate is substitutedfor methyl bromo acetate, there is obtained 5-benzyl-(7-bromo 4oxo-4,5-dihydrothieno- [3,2-c]-pyridine)-acetate orS-phenethyl-(7-bromo-4-oxo- 4,5-dihydrothieno[3,2-c1-pyridine) acetate,respectively.

EXAMPLE 12 5-Methyl-4-oxo-4,S-dihydrothieno 3,2-c] -pyridine, 1,5-

naphthalene disulfonic acid salt To a solution of 1.5 g. of4-oxo-4,5-dihydrothieno- [3,2-c1-pyridine in 30 ml. of dimethylformamideis added 0.5 g. of a 50% emulsion of sodium hydride. After stirring for30 minutes, 3 ml. of methyl iodide is added and stirred an additionalhour. The addition of 200 ml. of water does not produce a precipitate.The mixture is extracted four times with chloroform and evaporated togive an oily precipitate which is extracted with 2x 5 ml. of 2.5 Nhydrochloric acid. The acid solution is made basic with ammoniumhydroxide and the product extracted with ether. The ether is evaporatedand a methanol solution of 1.5-naphthalene disulfonic acid added. Theresulting precipitate is recrystallized from methanol, m.p. 256257 C.

When benzyl chloride, ethyl bromide or dimethylaminoethylchloride issubstituted for methyl iodide, there is obtained5-benzyl-4-ox0-4,S-dihydrothieno [3 ,2-c] -pyridine, 5-ethyl 4oxo-4,5-dihydrothieno[3,2-c]-pyridine, 5-dimethylaminoethyl-4-oxo 4,5dihydrothieno[3,2-c]-pyridine, respectively.

EXAMPLE 13 7-Bromo-4-methoxythieno [3 ,2-c] -pyridine To 1.5 g. of7-bromo-4-chlorothieno[3,2-c]pyridine in 50 m1. of methanol is added 1.5g. of sodium methoxide. The resulting mixture is heated under reflux for70 hours. The mixture is filtered and the filtrate evaporated and theresidue washed with water. Crystallization from methanol, yields theproduct, m.p. 91-94 C.

EXAMPLE 14 7-Bromo-4-benzyloxythieno 3,2-c] -pyridine A sample of 2.0 g.of 50% sodium hydride emulsion is washed with ether to remove theemulsifying oil. To this is added 25 ml. of benzyl alcohol. When all thesodium hydride has reacted, 2.5 g. of4-chloro-7-bromothieno[3,2-c]-pyridine is added and the mixture heatedon the steam-bath for 40 hours. 200 ml. of water is added and shaken.The water layer is decanted and another 200 ml. of water is added,shaken and then decanted. The solid remaining is recrystallized fromacetone by the addition of water. It is recrystallized from hexane, m.p.8486 C.

21 When phenethanol is substituted for benzyl alcohol, there is obtained7-bromo-4-phenethoxy[3,2-c]-pyridine.

EXAMPLE 15 4-Piperidino-7-bromothieno[3 ,2-c] -pyridine To 2.5 g. of7-bromo-4-chlorothieno[3,2-c]-pyridine is added 10 ml. of piperidine.After heating under reflux for 10 minutes, a precipitate appears. Theresulting mixture is heated for an additional 3 hours. Water is addedand the precipitate removed by filtration. The product is crystallizedfrom ethanol, m.p. 9597 C.

When ammonia, dimethylarnine, aniline, benzylamine, phenethylamine,azepine, morpholine or methylpiperazine is substituted for piperidine,there is obtained 7-amino-7- bromothieno[3,2-c]-pyridine, 4dimethylamino-7-bromothieno[3,2-c]-pyridine, 4 anilino 7 bromothieno[3,2-c]pyridine, 4-benzylamino 7 bromothieno[3,2-c]- pyridine,4-phenethylamino 7 bromothieno[3,2-c]-pyridine, 4-azepino 7bromothieno[3,2-c]-pyridine, 4-morpholino-7-bromothieno[3,2-c]-pyridineor 4-methylpiperazino-7-bromothieno [3,2-c]-pyridine, respectively.

EXAMPLE 16 7-Cyano-2-bromo-4-oxo-4,S-dihydrothieno[3,2-c]- pyridine To asolution of 1.76 g. of 7-cyano-4-oxo-4,5-dihydrothieno[3,2-c]-pyridinein 35 ml. of dimethylformamide at 60 C. is added 1.95 g. ofN-bromosuccinimide over minutes. After minutes, the solution is cooledand 75 ml. of water is added to precipitate a solid. This product iscrystallized from hot dimethylformamide, m.p. 303- 304 C.

When N-chlorosuccinimide, N-fluorosuccinimide or N- iodosuccinimide issubstituted for N-bromosuccinimide, there is obtained7-cyano2-chloro-4-oxo-4,S-dihydrothieno[3,2-c] -pyridine,7-cyano-2-fluoro 4 oxo 4,5 dihydrothieno[3,2-c]-pyridine or7-cyano-2-iodo-4-oxo-4,5- dihydrothieno[3,2-c]-pyridine, respectively.

EXAMPLE 17 7-Cyano-4-oxo-5-methyl-4,S-dihydrothieno[3,2-c1- pyridine Toa stirred solution of 1.96 g. of 7-cyano-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine in 30 ml. of dry dimethylformamide isadded 0.48 g. of 50% sodium hydride emulsion. When all the sodiumhydride has dissolved and the solution is at room temperature, 2 ml. ofmethyl iodide is added and the solution stirred for 2 hours at roomtemperature. Water is added and the resulting precipitate filtered,disolved in acetone, filtered, and the clear filtrate evaporated. Theresidue is crystallized from ethyl acetate to give the product, m.p.169-170" C.

When benzyl chloride, ethyl bromide or dimethylaminoethylchloride issubstituted for methyl iodide, there is obtained 7-cyano 4 oxo 5 benzyl4,5 dihydrothieno [3,2-c]-pyridine, 7-cyano-4-oxo 5 ethyl 4,5dihydrothieno[3,2-c]-pyridine or 7cyano 4 oxo 5 dimethylaminoethyl 4,5dihydrothieno[3,2-c]pyridine, respectively.

EXAMPLE 18 2,7-Dicyano-4-oxo-4, 5 -dihydrothieno [3 ,2-c] -pyridine Amixture of 4.6 g. of 2,7-dibrorno-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine, 6.0 g. of cuprous cyanide and 200 ml. ofdimethylformamide is heated under reflux for 18 hours. The mixture ispoured into a solution containing 60 g. of ferric chloride, 90 ml. ofwater, and ml. of concentrated hydrochloric acid. After 15 minutes at 65C., the solution is diluted with water to 600 ml. and the precipitatefiltered. Crystallization from acetone and Water gives a product with amelting point of 262-264 C.

When 2,7 di-bromo-4oxo-S-methyl-4,5-dihydrothieno [3,2-c]-pyridine,2,7-dibromo 4 oxo 5 benzyl-4,5- dihydrothieno[3,2-c1-pyridine issubstituted for 2,7 dibromo-4-oxo-4,S-dihydrothieno[3,2-c]-pyridine,there is obtained 2,7-dicyano-4-oxo-5-methyl 4,5 dihydrothieno[3,2-c]-pyridine or 2,7 dicyano-4-oxo-5-benzyl-4,5-dihydrothieno[3,2-c]-pyridine, respectively.

EXAMPLE 19 7-C arb oxy-4-oxo-4, S-dihydrothieno [3 ,2-c] -pyridine Sevengrams of 7-cyano-4-oxo-4,S-dihydrothieno[3,2-c]- pyridine is dissolvedin 28 ml. of concentrated sulfuric acid with stirring. The solution getswarm. After 2 hours, the temperature drops to room temperature andslowly, with stirring, 3 g. of crushed sodium nitrate is added. After anadditional 2 hours, the mixture is cautiously warmed on the steam-bathfor 7 minutes. After cooling, the solution is added to ice. Thecarboxylic acid separates and is removed by filtration. The product iscrystallized from dimethylformamide by the addition of acetone, m.p.344-346" C.

When 2,7-dicyano-4-oxo 4,5 dihydrothieno[3,2-c]- pyridine, 7-cyano 4oxo-5-methyl-4,S-dihydrothieno[3, 2-c]-pyridine or7-cyano-4-oxo-5-benzyl 4,5 dihydrothieno[3,2-c1-pyridine is substitutedfor 7-cyano-4-oxo- 4,5-dihydrothieno[3,2-c] -pyridine, there is obtained2,7-dicarboxy-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine, 7carboxy-4-oxo-5-methyl 4,5 dihydrothieno[3,2-c]-pyridine or7-carboxy-4-oxo-5-benzyl 4,5 dihydrothieno[3,2-c]- pyridine,respectively.

EXAMPLE 20 7-Chlorocarbonyl-4-chlorothieno[3,2-c] -pyridine Six grams of7-carboxy-4-oxo-4,5-dihydrothieno[3,2-c]- pyridine and ml. of phosphorusoxychloride are heated under reflux for 18 hours. The solution is pouredonto ice and stirred until the excess phosphorus oxychloride hasdecomposed. The acid chloride is crystallized by dissolving it inacetone and adding water and filtering the product rapidly, m.p. 119120C.

When 2,7-dicarboxy 4 oxo 4,5 dihydrothieno[3, 2-c]-pyridiue or3,7-dicarboxy 4 oxo 4,5 dihydrothieno[3,2-c1-pyridine is substituted for7-carboxyl-4-oxo- 4,5-dihydrothieno[3,2-c]-pyridine, there is obtained2,7- di(chlorocarbonyl) 4 -oxo 4,5 dihydrothieno[3,2-c]- pyridine or 3,7di (chlorocarbonyl)-4-oxo-4,5-dihydrothieno 3,2-c] pyridine,respectively.

EXAMPLE 21 7 -Carboxy-4-chlorothieno [3 ,2-c] -pyridine When the acidchloride in acetone solution is treated with water, the acid chloridecrystallizes, but in the filtrate is found some of the acid which can beobtained by evaporation of the filtrate. It changes form at 220-225 C.but does not become liquid until a temperature of 350- 355 C. isreached.

When 2,7-di-chlorocarbonyl- 4 chlorothieno[3,2-c]- pyridine issubstituted for 7-chlorocarbonyl-4-chlorothieno [3,2-c1-pyridine, thereis obtained 2,7-dicarboxy-4-chlorothieno [3 ,2-c] -pyridine.

EXAMPLE 22 4-Chlorothieno [3 ,2-c] -pyridine-7-carb oxamide To 100 mg.of the acid chloride is added 2 ml. of ammonium hydroxide. No solutionresults, but after 15 minutes the solid present is removed by filtrationand crystallized from dimethylformamide, alcohol and water, m.p.245-246" C.

When 2,7-di-chlorocarbonyl-4-chlorothieno 3,2-c] -pyridine issubstituted for 7-chlorocarbonyl-4-chlorothieno- [3,2-c1-pyridine, thereis obtained 4-chlorothieno-[3,2-c]- pyridine-2,7-di-carboxamide.

23 EXAMPLE 23 4-Aminothieno 3 ,2-c] -pyridine-7-carboxamide A mixture of3 g. of 4-chlorothieno[3,2-c]pyridine-7- carboxamide and 30 ml. ofliquid ammonia is heated at 150 C. for 18 hours in a bomb. Afterevaporation of the ammonia, the product is crystallized from hot water,from which it separates as a hydrate, m.p. 112ll3 C.

When dimethylamine, benzylamine or aniline is substituted for ammonia,there is obtained 4-dimethylaminothieno[3,2-c1-pyridine 7 carboxamide,4-benzylaminothieno[3,2-c]-pyridine-7-carboxamide or 4-anilinothieno-[3,2-c]-pyridine-7-carboxarnide, respectively.

Which 4-chlorothieno[3,2-c]-pyridine 2,7 dicarboxamide is substitutedfor 4-chlorothieno[3,2-c]-pyridine-7- carboxamide, there is obtained4-aminothieno[3,2-c]-pyridine-2,7-di-carboxamide.

EXAMPLE 24 4-Piperidino-7-carbamylthieno 3,2-c] -pyridine To 500 mg. of4-chlorothieno[3,2-c] -pyridine-7-carboxamide is added ml. of piperidineand the mixture heated under reflux. Since a solution was not formed, 3ml. of dimethylformamide is added and the resulting solution heatedunder reflux for 3 hours. Water is added to the point of crystallizationand the crystals separated by filtration and crystallized from ethanol,m.p. 205-207 C.

When azepine, morpholine, pyrrolidine or methylpi perazine issubstituted for piperidine, there is obtained 4-azepine 7carbamylthieno[3,2-c1-pyridine, 4-morpholino 7carbamylthieno[3,2-c]-pyridine, 4-pyrrolidino-7- carb amylthieno 3,2-c]-pyridine or 4-methylpiperazino-7- carbamylthieno [3 ,2-c] -pyridine,respectively.

When 4-chlorothieno[3,2-c]-pyridine 2,7 dicarboxamide is substituted for4-chlorothieno-[3,2-c]-pyridine-7- carboxamide, there is obtained4-piperidinothieno[3,2-c1- pyridine-2,7 di-carboxamide.

EXAMPLE 2S Methyl 4-chlorothieno [3,2-c] -pyridine-7-carboxylate Theacid chloride is warmed in methanol and upon cooling the estercrystallized, m.p. 1l01ll C.

When benzyl alcohol or phenol is substituted for methanol, there isobtained benzyl-4-chlorothieno[3,2-c]pyridine-7-carboxylate orphenyl-4-chlorothieno[3,2-c]-pyridine-7-carboxylate, respectively.

When 2,7-di-chlorocarbonyl-4-chlorothieno [3 ,2-c] -pyridine issubstituted for 7-chlorocarbonyl-4-chlorothieno- [3,2-c]-pyridine, thereis obtained dimethyl-4-chlorothieno 3 ,2-c] pyridine-2,7-di-carboxylate.

EXAMPLE 26 4-Chlorothieno [3,2-c] -pyridine-7-carboxanilide To 300 mg.of aniline is added 300 mg. of the acid chloride. After the vigorousreaction-has cooled, methanol is added and the solid removed byfiltration. The product is crystallized from dimethylformamide, methanoland water, m.p. 229-230 C.

When benzylamine, dimethylamine, azepine, morpholine, piperidine,pyrrolidine or methylpiperazine is substituted for aniline, there isobtained 7-benzylcarbamyl- 4 chlorothieno[3,2'c]pyridine, 7dimethylcarbamyl-4- chlorothieno[3,2 c]-pyridine,7-azepinecarbamyl-4-chlorothieno[3,2 c]-pyridine,7-morpholinocarbamyl-4-chlorothieno 3 ,2-c] -pyridine,7-piperidinocarbamyl-4-chlorothieno[3,2 c]-pyridine,7-pyrrolidinocarbamyl-4-chlorothieno[3,2 c]-pyridine ormethylpiperazinecarbamyl-4- chlorothieno [3 ,2-c] -pyridine,respectively.

When 2,7-di-chlorocarbonyl-4-chlorothieno [3 ,2-c] -pyridine issubstituted for 7-chlorocarbonyl-4-chlorothieno- 24 [3,2-c]-pyridine,there is obtained 4-chlorothieno[3,2-c]- pyridine-2,7-dicarboxanilide.

EXAMPLE 27 4-Chloro-7-hydroxymethylthieno 3 ,2-c] -pyridine To 400 ml.of ether is added 3.5 g. of lithium aluminum hydride. After stirring for45 minutes, a solution containing 12 g. of 7-chlorocarbonyl-4-chlorothieno[3,2-c]- pyridine in 500 ml. of ether is slowly added. Themixture is gently refluxed with good stirring for 18 hours. WaterEXAMPLE 28 4-Chloro-7-bromomethylthieno [3 ,2-c] -pyridine A solution of5 g. of 4-chloro-7-hydroxymethylthieno- [3,2-c]-pyridine in 50 ml. ofhydrobromic acid is heated under reflux for 6 minutes. After cooling,the crystals are separated by filtration and washed with acetone, m.p.217-219 C.

When 2,7-dihydroxymethyl-4-chlorothieno 3,2-c] -pyridine is substitutedfor 7-hydroxymethyl-4-chlorothieno- [3,2-c]-pyridine, there is obtained2,7-dibromomethyl-4- chlorothieno[3,2-c]-pyridine.

EXAMPLE 29 4-Chloro-7-ethylxanthylmethylthieno 3,2-c] -pyridine To 5 g.of 4-chloro-7-bromomethylthieno[3,2-c]-pyridine hydrogen bromide isadded 7 g. of ethyl xanthic acid potassium salt in ml. of water. Thismixture is stirred at room temperature and the white solid separated.This solid is crystallized from ethanol, m.p. 9l92 C.

When 2,7-dibromomethyl-4-chlorothieno[3,2 cJ-pyridine is substituted for7-bromoethyl-4-chlorothieno[3,2-c]- pyridine, there is obtained2,7-diethylxanthylmethyl-4- chlorothieno [3,2-c] -pyridine.

EXAMPLE 30 Bis-4-chloro-7-thiomethylthieno [3 ,2-c] -pyridine To asolution of 1.85 g. of4-chloro-7-ethylxanthylmethylthieno[3,2-c]-pyridine in 40 ml. of warmethanol is added 6 ml. of concentrated ammonium hydroxide. Afterstanding at room temperature for 48 hours, the bis compound is removedby filtration. The product is recrystallized from an alcohol, m.p.202203 C.

What is claimed is:

1. A compound of the formula m S Bax-N i wherein R is hydrogen, halogen,cyano or diloweralkylamino and R is hydrogen or loweralkyl orpharmaceutically acceptable salts thereof provided that R is nothydrogen or halogen when R is hydrogen.

2. The compound of Claim 1 wherein R is hydrogen and R is cyano.

3. The compound of Clain? 1 wherein R is dimethylamino and R ishydrogen.

4. The compound of Claim 1 wherein R is hydrogen and R is methyl.

5. The compound of Claim 1 wherein R is cyano and R is methyl.

6. The compound of Claim 1 wherein R is bromine and R is methyl.

26 References Cited UNITED STATES PATENTS G. THOMAS TODD, PrimaryExaminer US. Cl. X.R.

1. A COMPOUND OF THE FORMULA